The work described in this proposal addresses the clinical deficiency of the currently available oral treatments for hypothyroidism. Approximately 15% of persons suffering from hypothyroidism report insufficient symptomatic improvement from levothyroxine (T4, Synthroid) alone. This is thought to be related to a genetic variation in the enzyme that converts T4 to T3, the active form of thyroid hormone. Liothyronine (T3, Cytomel) is believed to be too rapidly absorbed and too short-lived to act as an effective complement to T4. If the value of combining T3 with T4 is to be realized for these patients, a controlled release product producing T3 plasma concentrations similar to normal (euthroid) will be needed. Euthroid plasma levels are important for achieving normal thyroid hormone concentrations in all tissues. The broad, long-term objective of this project is to provide patients a new product that can produce euthroid-like T3 levels with once daily oral dosing. The immediate goal is to test the feasibility of coordinating T3 with specific metals to produce proprietary complexes that provide a sustained release of T3 relative to Cytomel. The specific aims include (a) the synthesis and chemical characterization of a set of metallo-labeled T3 complexes and (b) the demonstration, in oral absorption studies in rats, of controlled release compared with a liothyronine control in one or more complexes. The metallo-T3 complexes are designed to extend the transit time through the gastrointestinal tract where T3 molecules gradually break free from the metal complex and enter the blood stream. This modulates the rate of delivery and thereby the rate of absorption. Metal coordinated T3 complexes will constitute new compositions of matter with market exclusivity. Moreover, the sustained release properties conferred onto T3 can be applied to other drugs that would benefit from modulated delivery. Finally, deuterium labeled T3 (T3-d3) will be used so that endogenous T3 can be distinguished from orally-dosed T3 by mass spectroscopy. This approach constitutes a significant practical advance when evaluating the absorption of thyroid hormones in vivo.